It is well established that HSV-1-induced corneal scarring (CS), and thus HSV-1-induced corneal blindness, are the result of immune responses triggered by the virus. The exact identity of the immune responses, including the fine specificity of the potentially harmful T-cell effectors expressing classic TCR12 antigen receptors that lead to CS remains an area of intense controversy. The vast majority of non-ocular HSV infections are either entirely asymptomatic or so mildly symptomatic as to go almost completely unrecognized. In contrast, symptomatic eye disease after HSV-1 reactivation is a major cause of corneal disease and blindness. The damaging effects of pre-existing immune responses that are manifested during recurrent infections is one rational explanation for the clinical observation that CS in humans is much more likely to occur following recurrent HSV infections rather than on primary infections. Our previous (Appendix 1) and preliminary results demonstrate an absence of CD8+ T cells in the cornea of mice infected with HSV-1. This absence of CD8+ T cells in the eyes of infected mice was observed irrespective of the strain of virus used for infection or the strain of mouse infected. Notably, however, we have found that infection of mice that have been immunized with one of the HSV-1 glycoproteins, gK, both exacerbates CS and results in the presence of CD8+CD25+ cells in the cornea. The exacerbation of CS in the immunized mice is associated with the presence of gK antibody and that the CD8+ cells are detectable in the corneas of mice immunized with gK, but not with live virus vaccine or any of the other known HSV-1 glycoproteins. This exacerbation of disease by an existing immune response in mice is of particular interest as it would appear to mimic the clinical disease process. Based on the preliminary data we have now generated, we hypothesize that, in unimmunized mice, viral gK acts to block induction of CD8+CD25+ T cells in the cornea of infected mice. In immunized mice, the gK-specific antibody binds the viral gK and masks the sites required for its inhibitory effects on the CD8+ T cells. Thus, "antigenic masking", independent of MHC class I or any other viral gene(s) in gK-immunized mice, leads to the stimulation of CD8+CD25+ T cells in the cornea of infected mice. The subsequent increase in the population of CD8+CD25+ T cells in the cornea leads to exacerbation of CS. We propose to test this hypothesis through the following Specific Aims: Aim 1: Confirm the hypothesis that anti-gK antibody play a major role in the induction of CD8+CD25+ T cells in the cornea of gK-immunized mice. Aim 2: Confirm the hypothesis that, in gK-immunized mice, the presence of CD8+CD25+ T cells in the cornea is responsible for exacerbation of CS on HSV-1 infection. Aim 3: Map the gK region that is involved in stimulation of CD8+CD25+ T cells and exacerbation of CS.HSV-1 infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral-induced blindness. HSV-1-induced CS, also broadly referred to as herpes stromal keratitis (HSK), can lead to blindness;thus, HSV-1 is the leading cause of corneal blindness due to an infectious agent in developed countries. In addition to necrotizing stromal keratitis, ocular infection with HSV-1 can cause eye disease ranging in severity from blepharitis, conjunctivitis, and dendritic keratitis, to disciform stromal edema. In the U.S., approximately 500,000 people suffer recurrent ocular HSV episodes annually, requiring doctor visits, medication, and, in severe cases, corneal transplants. We have shown for the first time that one of more than 80 genes of HSV-1 exacerbates eye disease in ocularly infected mice. We now plan to determine the mechanism of gK induced corneal scarring mice. These studies should reveal the type or combination of types of immune response that induces eye disease.